2. Academic Validation
  3. Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment

Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment

  • J Med Chem. 2024 Dec 26;67(24):22039-22054. doi: 10.1021/acs.jmedchem.4c01979.
Yongzhi Chen 1,  Kunyu Lu 2,  Binhao Rong 2,  Yuanmei Wen 1,  Guanguan Li 3,  Shuo Li 1,  Deyin Guo 4,  Qifan Zhou 1,  Shuwen Liu 2 5,  Xumu Zhang 1
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Shenzhen AntiV Pharma Co., Ltd., Shenzhen, Guangdong 518081, China.
  • 4 Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
  • 5 State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
PMID: 39658517 DOI: 10.1021/acs.jmedchem.4c01979
Abstract

The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of Antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301 exhibited an excellent anti-influenza activity (EC50, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent Endonuclease Inhibitor for further clinical research.

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